Clinico-Genomic Characterization of Patients with Metastatic Urothelial Carcinoma in Real-World Practice Identifies a Novel Bladder Immune Performance Index (BIPI)

Abstract Purpose: This retrospective analysis of the largest available clinico-genomic database used de-identified patient-level electronic health record-derived real-world data (RWD) combined with FoundationOne® comprehensive genomic profiling (CGP) to characterize patients with metastatic urothelial carcinoma (mUC) treated in the real-world setting, detect potential biomarkers, and develop a bladder immune performance index (BIPI). Experimental Design: Patients with mUC who started front-line single-agent immune checkpoint inhibitors (ICIs) and an unmatched group treated with front-line platinum-based chemotherapy between January 1, 2011 and September 30, 2019 were selected. Clinical and genomic data were correlated with overall survival (OS). A novel BIPI predicting outcome with ICIs was developed using machine learning methods and validated using data from a phase II trial (NCT02951767). Results: In ICI-treated patients (n=118), high tumor mutational burden (≥10 mutations/megabase) was associated with improved OS (HR 0.58 [95% CI, 0.35–0.95]; P=0.03). In chemotherapy-treated patients (n=268), those with high APOBEC mutational signature had worse OS (HR 1.43 [95% CI, 1.06–1.94]; P=0.02). Neither FGFR3 mutations nor DNA damage-repair pathway alterations were associated with OS. A novel BIPI combining clinical and genomic variables (non-metastatic at initial diagnosis, normal or above normal albumin level at baseline, prior surgery for organ-confined disease, high TMB) identified ICI-treated patients with longest OS and was validated in an independent dataset. Conclusions: Contemporary RWD including FoundationOne® CGP can be used to characterize outcomes in real-world patients according to biomarkers beyond PD-L1. A validated, novel clinico-genomic BIPI demonstrated satisfactory prognostic performance for OS in patients with mUC receiving front-line ICI therapy.